The long term goal of this proposed research is to elucidate the mechanisms of programmed cell death (apoptosis) in normal and malignant T cells. Apoptosis by anti-CD3 through the calcium signals in thymomas and T cell hybridomas may relate to negative selection during T cell development. Little is known regarding the mechanisms of apoptosis in these cells. It is also not clear why some tumor cells treated similarly are resistant to programmed cell death. Nur77 protein, an orphan steroid receptor, is induced by anti-CD3 in lymphomas and hybridomas sensitive to cell death but not in some other lymphomas insensitive to the same treatment. Intervention of the Nur77 protein function by a dominant negative mutant protects the sensitive cells from apoptosis. Cyclosporin A, an immune suppressive drug can suppress the activation induced apoptosis and at the same time, inhibits Nur77 protein expression. Glucocorticoid, which can induce cell death differentially among the different lymphomas and thymomas, rescues anti- CD3 cell death by inhibiting Nur77 expression. Thus, Nur77 expression correlates with anti-CD3 induced cell death and seems to be a master regulator of activation induced apoptosis. We will use T cell hybridomas, thymomas and lymphomas as well as transgenic mice to understand the process of apoptosis. Specifically, we will answer the following questions: i) What is the role of Nur77 during T cell development, in particular during negative selection? ii) Is prolonged Nur 77 expression sufficient to initiate cell death in the insensitive lymphomas or in thymocytes? iii) What is the relationship between Nur 77 and other proteins involved in apoptosis? iv) What are the downstream gene(s) regulated by Nur77? The above aims should lead to elucidation of how apoptosis occurs and why some tumor cells are insensitive to cell death. The information obtained might lead us to devise a mean to induce death in tumor cells and to halt the onset of cancer and AIDS.